Mechanisms Regulating Reduced c-Kit-Dependent EAE Susceptibility in Male SJL Mice

描述(申请人提供)：多发性硬化症(MS)，中枢神经系统(CNS)最常见的炎症性疾病，影响全球超过250万人。MS的特点是中枢神经系统血管周围炎症、神经纤维脱髓鞘和轴突损伤。当运动和感觉冲动通过大脑或脊髓的脱髓鞘区域时，其结果是中断，通常会导致视觉障碍、大小便失禁以及感觉和运动障碍。据估计，这种疾病在女性中的患病率至少是男性的三倍，尽管存在遗传、激素和免疫反应的差异，但这种性别偏见的基础仍然不完全清楚。多发性硬化症本质上被认为是自身免疫的，髓鞘特异性的CD4+Th1和Th17细胞是中枢神经系统炎症的主要协调者。据推测，这些细胞最初在外周淋巴器官被激活，但必须穿过相对不通透的血脑屏障(BBB)才能在中枢神经系统重新激活。其他渗透或驻留在中枢神经系统的先天免疫细胞会导致炎症介导的神经损伤。这些事件中的许多最初是通过研究类似的、尽管不完美的多发性硬化症啮齿动物模型-实验性变态反应性/自身免疫性脑脊髓炎(EAE)来定义的。肥大细胞是存在于大多数组织中的粒细胞，是对女性疾病严重程度起重要放大作用的天然细胞之一。携带编码SCF受体cKit的Kit突变的小鼠无法发育肥大细胞，并已被用于研究肥大细胞在复发-缓解EAE模型中的作用。我们先前证明雌性SJLW/WV小鼠表现出减弱的EAE，这是一种依赖于肥大细胞的表型。然而，雄性SJLW/WV小鼠的病情恶化，表明肥大细胞或其他与c-kit相关的缺陷在雄性小鼠中是病理性的。这不是由于野生型和野生型雄性之间的血清睾酮水平不同，没有显示出显著的差异。对于这些观察结果，至少有两种解释：i)在性激素的影响下，男性肥大细胞与女性肥大细胞相比，在疾病背景下表现出截然不同的反应；和/或ii)c-kit的配体干细胞因子协同发挥神经保护作用。 含有睾丸素，它能最大限度地减少中枢神经系统的免疫损伤。这项研究的具体目的是：1)比较导致野生型和CKITW/WV雄性小鼠发生EAE的事件(例如，外周T细胞启动、炎症细胞进入中枢神经系统、局部中枢神经系统炎症反应)，以确定c-kit信号在哪里发挥保护作用2) 确定肥大细胞或其他c-kit相关因素是否以及如何改变男性的疾病易感性。

DESCRIPTION (provided by applicant): Multiple sclerosis (MS), the most common inflammatory disease of the central nervous system (CNS), affects more than 2.5 million people worldwide. MS is characterized by perivascular inflammation in the CNS, demyelination of nerve fibers as well as axonal damage. The resulting interruption of motor and sensory impulses as they pass through demyelinated regions of the brain or spinal cord often leads to visual disturbances, incontinence as well as sensory and motor disturbances. The prevalence of this disease is estimated to be at least three times greater in females than males and while genetic, hormonal and immune response differences have been implicated, the basis for this gender bias is still not fully understood. MS is considered to be autoimmune in nature and myelin-specific CD4+ Th1 and Th17 cells are major orchestrators of the CNS inflammation. It is assumed that these cells are initially activated in peripheral lymphoid organs but must cross the relatively impermeable blood-brain barrier (BBB) to become reactivated in the CNS. Other innate immune cells that infiltrate or reside in the CNS contribute to inflammation-mediated neurological damage. Many of these events have been initially defined by studying the similar, albeit imperfect rodent model of MS, experimental allergic/autoimmune encephalomyelitis (EAE). Mast cells are granulocytes that reside in most tissues and are among the innate cells that exert an important amplifying effect on disease severity in females. Mice bearing mutations in Kit, which encodes the SCF receptor, ckit, fail to develop mast cells and have been used to study the role of mast cells in a relapsing-remitting EAE model. We previously demonstrated that female SJLW/Wv mice exhibit attenuated EAE, a phenotype dependent on mast cells. However, male SJLW/Wv mice have exacerbated disease, indicating either mast cells or other c-kit related defects are pathologic in males. This is not due to disparate serum testosterone levels between wild type and ckitW/Wv males, which show no significant differences. There are at least two explanations for these observations: i) Male mast cells, under the influence of sex hormones such as testosterone, show distinct responses in the context of disease compared to female mast cells; and/or ii) SCF, the ligand for c-kit, exerts a neuroprotective effect in concert with testosterone that acts to minimize immune-mediated damage in the CNS. The specific aims of this study are: 1) Compare the events (e.g. T cell priming in the periphery, inflammatory cell entry to the CNS, local CNS inflammatory responses) that lead to development of EAE in wild type versus ckitW/Wv male mice to determine where c-kit signals exert their protective influence 2) Identify whether and how mast cells or other c-kit related factors alter disease susceptibility in males.